Although the importance of plasma protein binding in drug disposition and effects is recognized, many specific questions persist. A significant impairment in plasma protein binding of drug is observed in certain disease states including various renal and hepatic diseases, but in most instances the the cause of this impairment is not evident and in some cases the clinical consequences are not clear. Administration of certain highly bound drugs with a displacing agent sometimes results in an intensification of pharmacologic effect and serious toxicity. In both cases a pharmacokinetic basis has been proposed to explain the clinical observations but these proposals are preliminary and require considerable critical examination. One would expect that factors that affect plasma protein binding would also affect tissue binding of drugs. Whether this is true is not known. Experimental approaches to answer, at least in part, many of these questions can be greatly facilitated by using animal models. Accordingly we propose to study the plasma protein binding, tissue binding and pharmacokinetics of several drugs in rats with altered plasma protein binding because of chemically or surgically induced renal or hepatic lesions or because of pre-treatment with agents known to displace drugs from plasma protein binding sites. The drugs to be studied are diazepam, phenytoin and sulfisoxazole; all are substantially bound to plasma proteins in the rat.